We are proposing the collection of pilot data for planning a more definitive epidemiological investigation of genetic protective factors in the families of individuals aged 70 years and older, with more than 20 pack-years of smoking who have not been diagnosed with lung cancer, the extremely exposed extremely resistant aged survivors (ERAS). Balmain and Nagase (1998) developed a model of differential resistance to cancer based on studies in mice and posited application to humans. This proposed study represents a novel genetic epidemiologic approach to test their model in the human setting. We will sample 100 probands from an existing registry of 216,022 elderly Pennsylvanians >= 70 years, on a prescription plan, 7-10 percent (15,581) of whom are current smokers (Pharmaceutical Assistance Contract for the Elderly (PACE) Program, 1999). We will test the feasibility of enrolling family members to participate in this study. We will document the type and structure of the families, and address the issues of familial aggregation of a lung-cancer resistant phenotype. With the ERAS probands, we will ascertain a sample enriched for 'protected' persons. We will provide descriptive statistics of ERAS in the PACE population, and in our sample. We will genotype the Myeloperoxidase (MPO) enzyme in probands and first-degree relatives. MPO transforms precarcinogens in tobacco smoke. Individuals who inherit two copies of the low activity allele (-463A) are reported to be at a reduced risk of lung cancer. Combined segregation and linkage analyses, together with generalized estimating equations, will be used to explore the mode of inheritance of hypothesized protective factors and characterize the association between the ERAS phenotype, the MPO genotype and selected demographic, medical and family history variables. Pilot data are sought to provide: a) an indication of a putative protective gene exhibiting Mendelian inheritance, b) an opportunity to model genetic resistance incorporating MPO genotypic data, and c) information needed for the efficient design of a subsequent study to examine "gene x gene" and "gene x environment" interactions. Evidence for genetic protection is sought primarily to increase understanding of the biology of lung cancer. The proposal does not imply that those with the putative resistant marker can smoke safely, an unwarranted conclusion given the other deleterious effects of cigarette smoking. Understanding mechanisms of resistance could suggest new preventive measures.